Hereditary hemochromatosis (HH) is an autosomal recessive disorder characterized by a progressive accumulation of hepatic iron and is one of the most common inherited diseases among Caucasians with an estimated prevalence of 1 in 250 and a heterozygote carrier rate of 8%10% in the white population. If left untreated irreversible organ damage, cardiomyopathy, diabetes mellitus, cirrhosis and hepatocellular carcinoma can occur in the 4th or 5th decade of life. Nearly all cases of hemochromatosis are due to a homozygous missense mutation in the HFE gene that changes amino acid residue 282 from a cysteine to a tyrosine (C282Y). However, there is only partial penetrance of this mutation and many C282Y homozygotes are asymptomatic. Full clinical penetrance, such as marked organ damage, is much less common and may depend on ethnic, environmental or genetic factors. The presence of one or more disease modifying genes has been postulated but has yet to be proven. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression by pairing with partially complementary target sequences in the 3' untranslated regions of messenger RNAs (mRNAs) to promote mRNA degradation and/or block translation. Recent studies have shown that levels of many circulating serum miRNA are elevated in patients with a variety of liver diseases and pathologies including HCC, HBV and liver cirrhosis, therefore serum miRNAs represent a new type of diagnostic and prognostic biomarker, and potential therapeutic target for several liver diseases. The role of miRNAs in HH is uncharacterized, although a liver specific miRNA miR-122 was recently shown to be involved in mammalian iron homeostasis by repressing the expression of hepcidin and its activators, the Hfe and Hjv genes in a mouse model of hemochromatosis. We are proposing a multifaceted approach to identify novel serum biomarkers, serum hepcidin levels and miRNA gene expression profiles that underlie potential iron homeostasis regulatory mechanisms. The proposed studies are feasible, will harness the vast resources of the HEIRS Study and will provide a unique opportunity to determine novel mechanisms involved in the penetrance of the C282Y HFE mutation.